HIV-associated dementia (HAD) involves destruction of neurons and synapses. Although it is agreed that brain inflammatory cells, including brain microglia and invading blood monocytes, participate in this CNS-damaging pathway by release of neurotoxins, the underlying mechanisms to account for neuropathogenesis of HAD remain uncertain. We have recently found a novel class of neurotoxins released by HIV-infected mononuclear cells. Extensive background study shows that this neurotoxin family is found in the cerebrospinal fluid (CSF) of HIV/AIDS volunteers and is closely associated with degrees of cognitive impairment. In order to uncover fundamental immuno-pathologic mechanisms of HAD, we will explore the HIV-elicited neurotoxin by examining its structural features, its mechanisms of action, and its ability to predict cognitive decline among HIV/AIDS volunteers. Further study will consider the effect of HAART on this CSF biomarker. This work represents transformational research that will help to delineate an immune pathway common to HAD and to other forms of dementia and will contribute to the development of neuroprotective treatments, which do not yet exist.